Leishmaniasis is the collective name for various tropical diseases, which are caused by flagellates of the leishmania species and are transmitted by various blood-sucking insects. The manifestations of leishmaniasis can be visceral (kala-azar), mucocutaneous (American leishmaniasis) or cutaneous (Aleppo boil or diffuse skin leishmaniasis). The incubation time ranges from weeks to months. A very high mortality rate is observed in untreated cases, especially in the case of kala-azar and the American leishmaniasis
Five-valent antimony compounds are the agent of choice in the standard therapy for the treatment of leishmaniasis diseases, such as sodium stilbogluconate, and aromatic diamidines which must be administered by parenteral injection. This not only leads to serious side effects because of the high toxicity of these materials, but also harbors the risk of infection.
The suitability of alkyl phosphocholines, especially hexadecyl phosphocholine (miltefosin) for the oral and topical treatment of leishmaniasis, was described for the first time by Eibl et al. in German patent application No. 4,132,344 and in European application No. 534,445, both of which were filed in 1991.
Numerous other authors describe the treatment of leishmaniasis with alkyl phosphocholines as a new class of medicinal drugs with remarkable antiprotozoal effectiveness. For example, T. Jha et al., Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis, N. Engl. J. Med. (1999), 341(24), 1795-1800 reported a study with 120 patients, to whom 50 to 150 mg of miltefosin per day was administered over a period of several weeks. In a pilot trial. Sundar et al., Oral treatment of visceral leishmaniasis with miltefosine, Ann. Trop. Med. Parasitol. (1999), 93(6), 589-597 observed the oral use of 100 to 200 mg of miltefosin per day in the case of visceral leishmaniasis.
Miltefosin is difficult to handle, because it is very hygroscopic, although it can be obtained in dry form as crystalline platelets with a defined melting point over 200° C. The absorption of water molecules can lead to an increase in weight of up to 30%, to a lowering of the melting point and to an agglomeration and lumping of crystals. Water-containing miltefosin cannot be adequately further processed into pharmaceutical preparations such as tablets, capsules or sachets. In particular, the flowability of water containing miltefosin is inadequate. However, a satisfactory flowability is one of the indispensable prerequisites for the production of pharmaceutical compositions on an industrial scale.
In addition, anhydrous miltefosin has an appreciable tendency to develop electrostatic charges, especially when it is stirred in the dry state. The flowability of electrostatically charged miltefosin is also inadequate for further processing into solid pharmaceutical compositions. Moreover, electrostatic charging is always associated with appreciable safety concerns because of the risk of explosions as well as damage to sensitive electronic parts.
To get around the above-mentioned problem during the production of pharmaceutical compositions containing solid miltefosin, Eibl et al. proposed that miltefosin be applied to the surface of silica particles in that a suspension of 1 part by weight of silica in a solution with 1 by weight of miltefosin is evaporated to dryness. The flowability of the solid dispersion, obtained in accordance with the proposal of Eibl et al., is in fact adequate for filling capsules at least on a laboratory scale. However, the method described by Eibl et al. is based on the use of a highly volatile solvent which, at the same time, because of the risk of electrostatic charging, is not flammable. For all practical applications, the only solvents, which are known in the art and fulfill these requirements, are methylene chloride and chloroform. However, halogenated hydrocarbons, especially chloroform, are classified as toxic and carcinogenic compounds. Furthermore, halogenated hydrocarbons accumulate in fatty tissue and are broken down only slowly.
It was described in patent publication No. WO 99/37289 that the above-mentioned problems can be solved by physically mixing an alkyl phosphocholine, especially hexadecyl phosphocholine with at least one flow promoter and/or lubricant, selected from the group of finely divided silica, talc, magnesium stearate and mixtures thereof, and at least one filler, from the group of lactose, microcyrstalline cellulose and mixtures thereof.
In accordance with publication WO 99/37289, it is possible, simply by mixing alkyl phosphocholines, especially miltefosin, a flow promoter and/or a lubricant and at least one filler, to obtain a solid pharmaceutical mixture with a flowabililty, which is adequate for further processing, especially into tablets, capsules or sachets.
In accordance with WO 99/37289 the pharmaceutical composition can be filled into capsules, preferably hard gelatin capsules, or pressed into tablets or effervescing tablets or, as a beverage or effervescent mixture, filled into sachets.
The miltefosin content per dose unit ranges from 10 to 800 mg, especially from 10 to 500 mg and particularly from 50 to 250 mg. The most preferred content ranges from 50 to 150 mg.
The production of miltefosin is described in detail in the examples for hexadecyl phosphocholine in the German patent application No. 4,132,344. Further methods for producing and purifying miltefosin are described in the German patent applications Nos. 2,752,125, 3,641,379, 3,641,491, 4,013,632, and 3,641,377.